The goals of this project are to identify novel genes involved in innate immunity and to determine if polymorphisms in some of these genes regulate the innate immune response to lipopolysaccharide (LPS), Staphylococcus aureus, and Aspergillus fumigatus infection in humans. We have previously shown that polymorphisms in TLR4, the receptor for LPS, are associated with hyporesponsiveness to inhaled LPS in mice and humans. We have also shown that these same polymorphisms predispose humans to Gram negative sepsis and protect them from atherosclerosis. However, our previous findings also demonstrate that sequence variants of TLR4 account for only a portion of the LPS phenotype in either mice or humans and that other genes are also involved in regulating the response to LPS. The role of host susceptibility in the initiation and severity of infections caused by Gram negative and Gram positive bacteria is incompletely understood. The overall goal of our sepsis project is to further understand why some individuals develop infection, and of those with bacteremia, why only some go on to have adverse outcomes. Similarly, very little is known about the host?s innate immune response to Aspergillus fumigatus, a fungal pathogen that causes invasive pulmonary aspergillosis in immunocompromized hosts. The overall hypothesis of this research program is that polymorphisms of genes identified either by genetic or genomic techniques following a challenge with a microbial toxin or a live organism in model systems (mice, C. elegans, and cell culture) regulate the pathophysiologic response to innate immune stimuli in humans. To test this hypothesis, gene expression and positional cloning studies will be conducted in mice and their genetic relevance will be tested in humans. We will also use RNA interference (RNAi) in two model systems, mammalian tissue culture and the nematode C. elegans, to test the physiologic and biologic importance of these genes.